Although various chemotherapeutic agents such as cisplatin and its derivatives can effectively cure patients with various types of cancer, the clinical success is compromised by the emergence of drug resistance and toxic side effects [B. Stordal, et al, Cancer Treat. Rev. 2007, 33, 688]. Breast cancer represents the most common diagnosed female malignancy and the second leading cause of women death worldwide. Treatments including surgery, radiotherapy, chemotherapy and endocrine therapy are effective at the early stage. For recurrent and metastatic breast carcinoma, available treatment options are limited, and in most cases, chemotherapy remains the only choice. Chemotherapeutic agents, such as cisplatin and its derivatives, doxorubicin, fluorouracil and monoclonal antibody trastuzumab are commonly used and usually given in the form of combinational chemotherapy. However, the effects of these agents are not universal, and a large portion of patients develop resistance. Moreover, side effects including induction of life-threatening toxicity are commonly encountered. Therefore, there is a great urge for the development of new alternative chemotherapeutic agents with fewer side effects.
Therapeutic values of metallic gold and gold salts have been recognized thousands of years ago and its rational use in medicine began in early 1920s. In recent decades, various gold(III) complexes have been reported to exhibit cytotoxicities against a broad spectrum of tumor cells. However, their instabilities in physiological condition have limited their therapeutic usage [C. F. Shaw, Chem. Rev. 1999, 99, 2589]. In the design of physiologically stable anti-cancer gold(III) complexes, Che and co-workers have employed strongly chelating porphyrinato ligands to stabilize a gold(III) ion [C.-M. Che, et al, Chem. Commun. 2003, 1718; R. W.-Y. Sun, et al, Coord. Chem. Rev. 2009, 253, 1682]. These gold(III) porphyrin complexes were found to display promising in vitro and in vivo anti-cancer activities towards a panel of cell lines including hepatocellular carcinoma, nasopharyngeal carcinoma, neuroblastoma and colon cancer. Yet, these complexes are poorly soluble in aqueous solution as hydrophilic substitution groups including (hydroxyl group) are absence in these complexes.
In addition to the gold(III) porphyrin complex, Wheelhouse et al [U.S. Pat. No. 6,087,493; hereafter “Wheelhouse”] has disclosed the use of porphyrin compounds and metalloporphyrin complexes contain pyridyl or quinolyl aldehyde derivatives to inhibit telomerase activity and hence, proliferation of cancer cells. Wheelhouse also disclosed that porphyrins which do not contain pyridyl or quinolyl aldehydes are inactive toward for the telomerase inhibition.
In the present invention, we have focused the use of hydroxy-substituted gold(III) porphyrin complexes as histone deacetylase inhibitors. These complexes are designed to block the active site of histone deacetylase and hence inhibit its activity.